Antitumor activity of TZT‐1027 (Soblidotin) against vascular endothelial growth factor‐secreting human lung cancer in vivo

Abstract

TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of antimicrotubule agents, including TZT-1027, was evaluated in both early-and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these agents. TZT-1027 exhibited potent antitumor activity against both early-and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity. (Cancer Sci 2003; 94: 826-833) ngiogenesis is the process whereby capillaries sprout from pre-existing blood vessels. The overall process is complicated, involving many cell types and biological functions, including endothelial cell activation, migration and proliferation.1) Previous studies have demonstrated that tumor angiogenesis is required for the growth and metastasis of primary solid tumors.2) This angiogenesis is influenced by the balance between the activation of promoting and inhibiting factors. The activation of promoting factors, such as basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF), released from hypoxic tumor cells, leads to neovascularization, while the activation of inhibiting factors generally causes tumors to undergo necrotic cell death.3) The importance of angiogenesis in human tumors was proved by recent reports demonstrating the vessel density in the tumor mass to be a prognostic factor for survival in people with various types of tumor. [4][5][6][7][8]

The novel microtubule-interfering agent TZT-1027 enhances the anticancer effect of radiation in vitro and in vivo

“…TZT-1027 is a novel antitumour agent that inhibits microtubule polymerisation and exhibits potent antitumour activity in preclinical models (Miyazaki et al, 1995;Kobayashi et al, 1997;Natsume et al, 2000Natsume et al, , 2003Natsume et al, , 2006Otani et al, 2000;Watanabe et al, 2000Watanabe et al, , 2006a. We investigated the effect of TZT-1027 on cell cycle progression with the use of tsFT210 cells, which can be synchronised in G 2 phase by incubation at 39.41C and consequent inactivation of Cdc2 (Osada et al, 1997;Tamura et al, 1999).…”

“…In vitro, it inhibits the growth of various human cancer cells at low concentrations . In vivo, TZT-1027 also manifests a broad spectrum of activity against various murine tumours as well as human tumour xenografts, without inducing a pronounced reduction in body weight (Kobayashi et al, 1997;Watanabe et al, 2000Watanabe et al, , 2006aNatsume et al, 2003Natsume et al, , 2006. Furthermore, the drug exhibited a potent antivascular effect on existing vasculature in an advancedstage tumour model (Otani et al, 2000).…”

Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

“…TZT-1027 showed antitumor activity in vivo against a hypervascular advanced-stage tumor from a VEGFtransfectant lung cancer cell line, whereas VCR and TXT did not. 10 The upregulation of TIMP3 by TZT-1027 is one possible mechanism for the superior antivascular activity of this drug, compared to that of taxanes and Vinca alkaloids.…”

“…7,10,15 TZT-1027 also showed potent antitumor activity against a vincristine-resistant cell line. 7 A recent investigation of the mode of action reported that TZT-1027-induced apoptosis and cell arrest in the G 2 /M phase that was independent of caspase-3 or bcl-2.…”

“…7 Superior antivascular activity resulting in the collapse of the tumor vasculature was demonstrated, compared with the activities of taxanes and Vinca alkaloids. [8][9][10] The first clinical phase I study of TZT-1027 was initiated in 1994, and another four studies have since been completed; a phase II study is currently ongoing. [11][12][13] The major toxicity was hematological, in the form of neutropenia and leukopenia.…”